MITOCHONDRIAL ETIOLOGIES OF PARKINSON'S DISEASE

我们的中心致力于解决帕金森病（PD）中线粒体DNA遗传异常的作用。PD是成人第二大最常见的神经退行性疾病，约有100万美国人患有PD。预期寿命缩短，生活质量受到PD的不利影响。虽然已经描述了突触核蛋白突变的罕见家族，但绝大多数病例的PD原因尚不清楚。传统的孟德尔遗传因素似乎没有显着的病因。此外，目前确定的环境风险因素似乎也发挥了最小的作用，影响发展中国家的风险。我们中心的研究人员首先阐明了遗传性线粒体DNA异常可能在PD中起致病作用并解释其散发性外观的假设。他们首先证明了PD中的线粒体复合物I合成缺陷。他们是第一个采用线粒体转基因细胞质杂交（“cybrid”）技术复制神经细胞，并使用cybrid技术证明PD中的复合物I合成缺陷是线粒体DNA异常的结果。我们的研究小组是第一个证明线粒体DNA（mtDNA）的遗传突变可能有助于在一个多代家庭中完全母系传播的PD，并且第一个提供证据证明PD中的母系传播占主导地位。我们中心的研究人员首次表明，胞质杂交体中的PD线粒体产生细胞内钙信号传导异常，氧化应激增加，线粒体膜电位降低，NF κ B基因活化增加，线粒体运动和形态改变。这些对细胞功能和存活的重要生物学后果可能代表PD mtDNA突变如何增加PD中神经元死亡风险的机制。这种科学进步的跟踪记录，加上线粒体DNA的遗传异常构成大多数PD病例的合理病因的知识，强调了本申请中建议的重要性。在本申请的四个项目中，我们将对PD受试者的线粒体DNA进行测序，表征PD中线粒体结构和功能的异常，阐明PD的遗传流行病学，并阐明线粒体功能障碍与神经元死亡之间的关系。这些研究的结果可能会导致临床前诊断程序和特定的治疗，以阻止PD中的神经元死亡。

Our Center is dedicated to resolving the role of inherited abnormalities in mitochondrial DNA in Parkinson's Disease (PD). PD is the second most prevalent neurodegenerative disorder of adults and afflicts about 1 million Americans. Life expectancy is shortened and quality of life is adversely affected by PD. While rare families with mutations in synuclein proteins have been described,, the cause of PD in the vast majority of cases is unknown. Traditional Mendelian genetic factors do not appear to contribute prominently to etiology. Furthermore, currently identified environmental risk factors also appear to play a minimal role in influencing the risk of developing PD. Investigators in our Center first articulated the hypothesis that inherited mitochondrial DNA abnormalities might play a pathogenic role in PD and account for its sporadic appearance. They were first to demonstrate a mitochondrial Complex I synthetic defect in PD. They were the first to adapt the mitochondrial transgenic cytoplasmic hybrid ("cybrid") technique to replicating neural cells and to use cybrid technology to demonstrate that the complex I synthetic defect in PD occurred as a consequence of abnormalities in mitochondrial DNA. Our group was the first to demonstrate that an inherited mutation in mitochondrial DNA (mtDNA) could contribute to PD in a multi-generational family with exclusively matrilineal transmission, and the first to provide evidence of a predominance of maternal transmission in PD. Investigators in our Center were the first to show that PD mitochondria in cybrids produced abnormalities in intracellular calcium signaling, increased oxidative stress, depressed mitochondrial membrane potential, increased NFkappaB gene activation and altered mitochondrial movement and morphology. These important biological consequences for cell function and survival may represent mechanisms of how PD mtDNA mutations increase risk of neuronal death in PD. This track record of scientific progress, coupled with the knowledge that inherited abnormalities of mitochondrial DNA constitute a plausible etiology for most cases of PD, underscore the significance of the proposals in this application. In the four Projects in this application we will sequence mitochondrial DNA in subjects with PD, characterize abnormalities of mitochondrial structure and function in PD, clarify the genetic epidemiology of PD, and elucidate the relationship between mitochondrial dysfunction and neuronal death. Results of these studies may lead to preclinical diagnostic procedures and specific therapies to halt neuronal death in PD.